KR20240026893A - Uses of heterocyclic inhibitors of ERK1/2 - Google Patents

Abstract

Provided is the use of heterocyclic inhibitors of ERK1/2 for treating cancer, particularly solid tumors. In particular, the ERK1/2 inhibitor is administered to a subject twice daily, once a week and is used to treat cancer, including non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, or colorectal cancer (CRC) (S )-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro2H-pyran-4-yl)amino)pyrimidine -4-yl)-1H-imidazole-4-carboxamide. In some embodiments, the cancer is MAPKm/MAPKi naive pan-tumor.

Description

Uses of heterocyclic inhibitors of ERK1/2

cross-reference

This application claims priority from U.S. Provisional Application No. 63/176,131, filed April 16, 2021, which is incorporated herein by reference in its entirety.

ERK1 and ERK2 (collectively “ERK1/2”) are related protein-serine/threonine kinases that participate, among others, in the Ras-Raf-MEK-ERK signaling pathway, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is believed to play a central role in regulating many fundamental cellular processes, including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism, and transcription. Activation of the MAPK pathway has been reported in numerous tumor types, including lung, colon, pancreas, kidney, and ovarian cancer. Therefore, substances that can reduce activation may be of interest for possible treatment.

ERK1/2 appears to be activated by MEK through phosphorylation of both threonine and tyrosine residues, namely Tyr204/187 and Thr202/185. Once activated, ERK1/2 catalyzes the phosphorylation of more than 100 serine/threonine residues of its substrates and activates both cytoplasmic and nuclear proteins involved in cell growth, proliferation, survival, angiogenesis, and differentiation, hallmarks of the cancer phenotype. . Therefore, it may be beneficial to target ERK 1 and ERK 2 to develop and use ERK1/2 inhibitors as a method to inhibit tumor growth.

Additionally, ERK inhibitors may have utility in combination with inhibitors of other kinases, such as MAPKs. Recently, researchers reported that dual inhibition of MEK and ERK by small molecule inhibitors had a synergistic effect and acted to overcome acquired resistance to MEK inhibitors. Hatzivassiliou et al., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther . 2012, 11, 1143-1154].

There is a need to develop dosing regimens that improve exposure, prolong ERK1/2 inhibition, and increase antitumor activity while maintaining an acceptable safety profile.

In a first aspect, the disclosure provides a method of treating cancer in a subject in need of treatment for cancer, the method comprising:

Compound 1 , or a pharmaceutically acceptable salt thereof, wherein Compound 1 is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating cancer, the salt of Compound 1 is a mandelic acid salt.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, It is administered in an amount of about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice daily, It is administered once a week (BID-QW).

In some embodiments of the method of treating cancer, the cancer comprises at least one cancer cell with one or more activating mutations in the MAPK pathway.

In some embodiments of the method of treating cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating cancer, the cancer is colorectal cancer (CRC), pancreatic adenocarcinoma (PDAC), cholangiocarcinoma cancer, appendix cancer, stomach cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, uterine cancer. , or acute myeloid leukemia (AML).

In some embodiments of the method of treating cancer, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, or colorectal cancer (CRC).

In some embodiments of the method of treating cancer, the cancer is MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive NSCLC, BRAFi treated V600 NSCLC, BRAFi treated V600 melanoma, or KRAS treated G12C. It is NSCLC.

In some embodiments of the method of treating cancer, a subject in need of treatment for cancer does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating cancer, the subject in need of treatment for cancer does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Citation by Reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

The novel features of the disclosure are set forth in detail in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description, and accompanying drawings, which set forth illustrative implementations in which the principles of the disclosure are utilized:
Figure 1 shows a plot of the simulated Compound 1 steady-state PK profile.

As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an “agent” includes a plurality of such agents, a reference to a “cell” includes reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, etc. . When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein. The term "about" when referring to a number or numerical range means that the stated number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases the number or numerical range is within the stated number or numerical range. It will vary from 1% to 15% of. The term “comprising” (and related terms such as “comprises” or “having”) refers to other specific embodiments, such as any composition of matter, composition, method, or process described herein. It is not intended to exclude “consisting of” or “consisting essentially of” features.

As used in the specification and appended claims, unless otherwise specified, the following terms have the meanings set forth below.

As used herein, the term “therapeutic agent” means an agent used to treat, combat, ameliorate, prevent or ameliorate an unwanted condition or disease in a patient. In some embodiments, a therapeutic agent, such as Compound 1, relates to the treatment and/or amelioration of cancer.

“Administration”, when used in conjunction with a therapeutic agent, means administering the therapeutic agent systemically or locally, such as directly into or onto a target tissue, or administering the therapeutic agent to a patient so that the therapeutic agent positively affects the tissue for which it is targeted. It means administering. Accordingly, as used herein, the term “administration,” when used in conjunction with a composition described herein, includes, but is not limited to, providing a composition into or on a target tissue; It may involve providing the composition to the patient systemically, such as by oral administration, such that the therapeutic agent reaches the target tissue or cells. “Administering” the composition can be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

As used herein, the term “animal” includes, but is not limited to, human and non-human vertebrates, such as wild, domestic, and farm animals. As used herein, the terms “patient,” “subject,” and “individual” are intended to include living organisms capable of developing a particular condition as described herein. Examples include humans, monkeys, cattle, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain cases, the human is an adult. In certain cases, the human is a child. In additional cases, the human is under 12 years of age. In certain cases, the human is elderly. In other cases, the human is over 60 years of age. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cattle. The experimental animal can be an animal model for a disorder, such as a transgenic mouse with hypertensive pathology.

“Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to its recipient.

The term “pharmaceutical composition” refers to a composition comprising at least one active ingredient, such that the composition can be tested for specified effective results in mammals (e.g., but not limited to, humans). Those skilled in the art will understand and recognize appropriate techniques to determine whether an active ingredient has the desired effective results based on the needs of the skilled artisan.

As used herein, a “therapeutically effective amount” or “effective amount” refers to: Refers to the amount of an active compound or pharmaceutical agent that induces a biological or medical response: (1) preventing disease; For example, preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but does not yet experience or exhibit pathology or symptoms of the disease; (2) inhibiting the disease; For example, inhibiting the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, and (3) improving disease; For example, ameliorating (i.e., reversing the pathology and/or symptoms of) a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder.

As used herein, the terms “treat,” “treated,” “treatment,” or “treating” refer to both therapeutic treatment in some embodiments and prophylactic measures in other embodiments, the purpose being Preventing or slowing down (reducing) an undesirable physiological condition, disorder or disease, or achieving beneficial or desired clinical results. For purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; Reduction in the severity of a condition, disorder or disease; stabilizing (i.e., not worsening) the state of a condition, disorder or disease; delaying the onset or slowing of the progression of a condition, disorder or disease; Improvement of a condition, disorder or disease state; and remission (whether partial or total), or enhancement or amelioration of the condition, disorder or disease, whether detectable or undetectable. Treatment involves inducing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. Prophylactic benefits of treatment include preventing the condition, delaying the progression of the condition, stabilizing the condition, or reducing the likelihood of developing the condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

As used herein, the term "substantially identical" refers to a powder x-ray diffraction pattern or differential scanning calorimetry pattern that is not identical to that shown herein but is within the limits of experimental error as considered by one of ordinary skill in the art.

Compound 1

(S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino )Pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

, or pharmaceutically acceptable salts thereof are disclosed herein.

In some embodiments, the salt of Compound 1 is a mandelic acid salt. In some embodiments, the salt of Compound 1 is a benzenesulfonic acid salt. In some embodiments, the salt of Compound 1 is a hydrochloride salt. In some embodiments, the salt of Compound 1 is p-toluenesulfonic acid salt.

In some embodiments, the salt of Compound 1 is a benzenesulfonic acid salt.

Treatment method

Disclosed herein is a method of treating cancer in a subject in need thereof comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, wherein Compound 1 is administered twice daily, once per week. It is administered once (BID-QW). Also disclosed herein is a method of treating a solid tumor in a subject in need of solid dose treatment comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, wherein Compound 1 is administered twice daily, It is administered once a week (BID-QW). In some embodiments, Compound 1 is administered for at least one 28-day cycle. In some embodiments, Compound 1 is administered for at least one 35-day cycle.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer (e.g., pancreatic cancer is pancreatic ductal adenocarcinoma, PDAC), salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

In some embodiments, the cancer is colorectal cancer (CRC), pancreatic adenocarcinoma (PDAC), cholangiocarcinoma cancer, appendix cancer, stomach cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, or uterine cancer.

In some embodiments, the cancer is a liquid tumor, hematological malignancy, or hematological cancer. In some embodiments, the cancer is leukemia, lymphoma, or melanoma. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the AML is relapsed and/or refractory AML. In some embodiments, the AML is FLT3 mutant AML.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the solid tumor is an advanced or metastatic solid tumor. In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, or colorectal cancer (CRC).

In some embodiments of the method of treating a solid tumor, the tumor is metastatic BRAF mutated melanoma; metastatic NRASmut or HRASmut advanced solid tumor; metastatic KRASmut colorectal cancer (CRC); metastatic KRASmut colorectal cancer (CRC); metastatic KRASmut non-small cell lung cancer (NSCLC); It is metastatic pancreatic adenocarcinoma (PDAC).

In some embodiments of the method of treating a solid tumor, the solid tumor is NSCLC, wherein the NSCLC is MAPKm/MAPKi naive NSCLC. In some embodiments of the method of treating a solid tumor, the solid tumor is NSCLC, wherein the NSCLC is BRAFi treated V600 NSCLC. In some embodiments of the method of treating a solid tumor, the solid tumor is NSCLC, wherein the NSCLC is KRAS treated G12C NSCLC.

In some embodiments of the method of treating a solid tumor, the solid tumor is pancreatic cancer, wherein the pancreatic cancer is MAPKm/MAPKi naive pancreatic cancer.

In some embodiments of the method of treating a solid tumor, the solid tumor is a MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating a solid tumor, the solid tumor comprises at least one cancer cell with one or more activating mutations in the MAPK pathway.

In some embodiments of the method of treating a solid tumor, the tumor is a mitogen activated protein kinase (MAPK) pathway driven cancer. In some embodiments of the method of treating a solid tumor, the cancer is a BRAF driven cancer. In some embodiments of the method of treating a solid tumor, the cancer is an HRAS driven cancer. In some embodiments of the method of treating a solid tumor, the cancer is a NRAS driven cancer.

dosage

In one aspect, the compositions described herein are used in the treatment of diseases and conditions described herein. Additionally, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment includes administering to the subject a therapeutically effective amount of a composition.

Dosages of compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum responding dose (MRD) for Compound 1, or a pharmaceutically acceptable salt thereof, can be determined in the examples described herein as well as through established animal and human testing protocols. For example, the toxicity and therapeutic efficacy of Compound 1, or a pharmaceutically acceptable salt thereof, can be determined by standard pharmaceutical procedures in cell culture or experimental animals, including, but not limited to, LD ₅₀ (lethality in 50% of the population). effective dose) and ED ₅₀ (therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of these compounds is preferably within a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. Dosages may vary within this range depending on the dosage form used and the route of administration utilized. Additional relative doses, expressed as a percentage of maximum response or maximum tolerated dose, are easily obtained through the protocol.

In some embodiments, the amount of a given preparation comprising Compound 1, or a pharmaceutically acceptable salt thereof, corresponding to such amount may vary depending on the molecular weight of the particular salt or form, the disease state and severity thereof, and that of the subject or host in need of treatment. will vary depending on factors such as identity (e.g., age, weight, gender), but will nonetheless encompass the case, including, for example, the specific agent administered, the type of liquid formulation, the condition being treated, and the subject or host being treated. It may be determined depending on the specific situation.

In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, as described herein is relative to the free base equivalent of Compound 1.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 200 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 150 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 100 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 50 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg to about 200 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg to about 150 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg to about 100 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg to about 200 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg to about 150 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150 mg to about 200 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in amounts of about 175 mg and about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175 mg to about 200 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225 mg to about 300 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225 mg to about 250 mg twice daily, once per week (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, has an amount of about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, About 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 Administered in amounts of about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg. do.

administration

Administration of the described Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the dosages described herein or at other dosage levels and compositions as determined and contemplated by the physician. In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a patient already suffering from the disease in an amount sufficient to cure the disease or at least partially halt or ameliorate the symptoms. Amounts effective for this use will vary depending on the patient's age, severity of the disease, previous therapy, the patient's medical condition, weight, and response to the composition, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trials.

In prophylactic applications, the compositions described herein are administered to patients who are predisposed to or at risk of a particular disease, such as cancer. This amount is defined as a “prophylactically effective amount or dose.” For these uses, the exact amount also depends on the patient's age, health status, weight, etc. When used in a patient, the effective amount for this use will depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the composition, and the judgment of the treating physician.

In certain embodiments where the patient's condition does not improve, at the discretion of the physician, administration of the compositions described herein may be administered chronically, i.e., over an extended period of time, e.g. It is administered throughout the lifespan of the patient. In other embodiments, administration of the composition continues until complete or partial response of the disease.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times per day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasting state. The fasted state refers to a subject being without food or fasting for a period of time. Typical fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasted state for at least 8 hours. In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasted state for at least 10 hours. In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasted state for at least 12 hours. In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject who has fasted overnight.

In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state. The eating state refers to the subject having eaten or eaten food. In certain embodiments, the composition is administered to a subject in a feeding state at 5 minutes after a meal, 10 minutes after a meal, 15 minutes after a meal, 20 minutes after a meal, 30 minutes after a meal, 40 minutes after a meal, 50 minutes after a meal, 1 hour after a meal, or 2 hours after a meal. do. In certain instances, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state 30 minutes after a meal. In other cases, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject in a fed state one hour after a meal. In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the subject with food.

The length of the treatment cycle depends on the treatment given. In some embodiments, the length of the treatment cycle ranges from 2 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 4 weeks. In some embodiments, the length of the treatment cycle is 3 weeks (or 21 days). In some embodiments, the length of the treatment cycle is 4 weeks (28 days). In some embodiments, the length of the treatment cycle is 5 weeks (35 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts 1, 2, 3, 4, or 5 weeks. In some embodiments, the treatment cycle lasts 3 weeks. In some embodiments, the treatment cycle lasts 4 weeks. In some embodiments, the treatment cycle lasts 5 weeks. The number of scheduled treatment doses within each cycle also depends on the drug being given.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in 28-day cycles. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over multiple 28-day cycles. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over at least two 28-day cycles. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over at least three 28-day cycles.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 1 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 8 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 15 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 22 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice daily on day 22 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, or 23-28 of a 28-day cycle. .

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in 35-day cycles. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over multiple 35-day cycles. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-35 of each 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 1 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 8 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 15 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 22 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 29 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice daily on day 29 of a 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in 28-day cycles. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over multiple 28-day cycles. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over at least two 28-day cycles. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least three 28-day cycles.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 1 of a 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 8 of a 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 15 of a 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 22 of a 28-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice daily on day 22 of a 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, or 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in 35-day cycles. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered over multiple 35-day cycles. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-35 of each 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 1 of a 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 8 of a 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 15 of a 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 22 of a 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on day 29 of a 35-day cycle. In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice daily on day 29 of a 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

Disclosed herein are methods of treating a solid tumor in a subject in need of treatment for a solid tumor, the method comprising: treating a solid tumor in a subject in need thereof;

Compound 1 , or a pharmaceutically acceptable salt thereof,

Here, Compound 1 is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating a solid tumor, the salt of Compound 1 is a mandelic acid salt.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. It doesn't work.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 300 mg twice daily, once per week (BID-QW). .

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 250 mg twice daily, once per week (BID-QW). .

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 150 mg twice daily, once per week (BID-QW). .

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, 50 mg, about 75 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg. , is administered in an amount of about 225 mg, or about 250 mg, twice a day, once a week (BID-QW).

In some embodiments of the method of treating a solid tumor, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, 50 mg, about 100 mg, or about 150 mg twice daily, once per week. It is administered once (BID-QW).

In some embodiments of the method of treating a solid tumor, the solid tumor comprises at least one cancer cell with one or more activating mutations in the MAPK pathway.

In some embodiments of the method of treating a solid tumor, the solid tumor is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating a solid tumor, the solid tumor is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating a solid tumor, the solid tumor comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating a solid tumor, the solid tumor has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating a solid tumor, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating a solid tumor, the solid tumor is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, or colorectal cancer (CRC).

In some embodiments of the method of treating a solid tumor, the solid tumor is MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive NSCLC, BRAFi treated V600 NSCLC, BRAFi treated V600 melanoma, or KRAS treated. It is a G12C NSCLC.

In some embodiments of the method of treating a solid tumor, a subject in need of treatment for a solid tumor does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating a solid tumor, the subject in need of treatment of a solid tumor does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating non-small cell lung cancer (NSCLC) in a subject in need of treatment for non-small cell lung cancer, said method comprising:

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle. do.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, and 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle. do.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28 of a 28-day cycle. day, and not administered on days 30-35.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice a day, once a week (BID-QW) ) is administered.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice a day, once a week (BID-QW) ) is administered.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice a day, once a week (BID-QW) ) is administered. In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg. It is administered in an amount of mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice per day. It is administered once a week (BID-QW).

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer comprises at least one cancer cell driven by deregulated ERK.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer is MAPKm/MAPKi naive pan-neoplastic(-) CRC/NSCLC, MAPKm/MAPKi naive NSCLC, BRAFi treated V600 NSCLC, or KRAS treated G12C NSCLC. .

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need of treatment for NSCLC does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need of treatment for NSCLC does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating melanoma in a subject in need of treatment, said method comprising:

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, and 23-28 of a 28-day cycle.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. Administered in amounts of mg, about 200 mg, about 225 mg, or about 250 mg twice daily, once a week (BID-QW),

In some embodiments of the method of treating melanoma, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice daily, per week. It is administered once (BID-QW).

In some embodiments of the method of treating melanoma, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating melanoma, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating melanoma, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating melanoma, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating melanoma, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating melanoma, the cancer is BRAFi treated V600 melanoma.

In some embodiments of the method of treating melanoma, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating melanoma, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating pancreatic cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating pancreatic cancer, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. , is administered in an amount of about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating pancreatic cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week. It is administered once (BID-QW).

In some embodiments of the method of treating pancreatic cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating pancreatic cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating pancreatic cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating pancreatic cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating pancreatic cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating pancreatic cancer, the cancer is MAPKm/MAPKi naive pancreatic cancer.

In some embodiments of the method of treating pancreatic cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating pancreatic cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating colorectal cancer (CRC) in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. It doesn't work.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. It is administered in amounts of mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating colorectal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg, twice daily, per week. It is administered once (BID-QW). ,

In some embodiments of the method of treating colorectal cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating colorectal cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating colorectal cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating colorectal cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating colorectal cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating colorectal cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating colorectal cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating colorectal cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating cholangiocarcinoma cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. Not administered.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and Do not administer on days 30-35.

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about It is administered in an amount of 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating cholangiocarcinoma cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg, twice daily, 1 It is administered once a week (BID-QW).

In some embodiments of the method of treating cholangiocarcinoma cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating cholangiocarcinoma cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating cholangiocarcinoma cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating cholangiocarcinoma cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating cholangiocarcinoma cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating cholangiocarcinoma cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating cholangiocarcinoma cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating cholangiocarcinoma cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating appendiceal cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. It doesn't work.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. It is administered in amounts of mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating appendiceal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, for a week. It is administered once (BID-QW).

In some embodiments of the method of treating appendiceal cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating appendiceal cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating appendiceal cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating appendiceal cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating appendiceal cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating appendiceal cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating appendiceal cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating appendiceal cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating gastric cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. , is administered in an amount of about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating gastric cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week. It is administered once (BID-QW).

In some embodiments of the method of treating gastric cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating gastric cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating gastric cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating gastric cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating gastric cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating gastric cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating gastric cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating gastric cancer, the subject in need of treatment does not experience grade 3, 4, or 5 adverse events during the 28-day cycle.

Disclosed herein are methods of treating esophageal cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating esophageal cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least one 28-day cycle.

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating esophageal cancer, Compound 1 or a pharmaceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. .

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. , is administered in an amount of about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating esophageal cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week. It is administered once (BID-QW).

In some embodiments of the method of treating esophageal cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating esophageal cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating esophageal cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating esophageal cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating esophageal cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating esophageal cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating esophageal cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating esophageal cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating head and neck cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. It doesn't work.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. It is administered in amounts of mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating head and neck cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg, twice daily, per week. It is administered once (BID-QW).

In some embodiments of the method of treating head and neck cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating head and neck cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating head and neck cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating head and neck cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating head and neck cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating head and neck cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating head and neck cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating head and neck cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating ovarian cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. It doesn't work.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30 of a 28-day cycle. -Do not administer on day 35.

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once weekly (BID-QW).

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. It is administered in amounts of mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating ovarian cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice daily, per week. It is administered once (BID-QW).

In some embodiments of the method of treating ovarian cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating ovarian cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating ovarian cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating ovarian cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating ovarian cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating ovarian cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating ovarian cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating ovarian cancer, the subject in need of treatment does not experience grade 3, 4, or 5 adverse events during the 28-day cycle.

Disclosed herein are methods of treating uterine cancer in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is not administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. No.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-days of a 28-day cycle. Not administered on day 35.

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once per week (BID-QW).

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg. , is administered in an amount of about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating uterine cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day, once a week. It is administered once (BID-QW).

In some embodiments of the method of treating uterine cancer, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating uterine cancer, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating uterine cancer, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating uterine cancer, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating uterine cancer, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating uterine cancer, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating uterine cancer, a subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating uterine cancer, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Disclosed herein are methods of treating acute myeloid leukemia (AML) in a subject in need thereof; The method is provided to a subject in need of treatment.

Compound 1 , or a pharmaceutically acceptable salt thereof;

Here, the compound is administered twice a day, once a week (BID-QW).

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. Not administered.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and Do not administer on days 30-35.

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 300 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 250 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to 150 mg twice daily, once weekly (BID-QW). .

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about It is administered in an amount of 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW).

In some embodiments of the method of treating acute myeloid leukemia, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50 mg, about 100 mg, about 125 mg, or about 150 mg, twice daily, 1 It is administered once a week (BID-QW).

In some embodiments of the method of treating acute myeloid leukemia, the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer.

In some embodiments of the method of treating acute myeloid leukemia, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments of the method of treating acute myeloid leukemia, the cancer comprises at least one cancer cell caused by deregulated ERK.

In some embodiments of the method of treating acute myeloid leukemia, the cancer has at least one mutation in RAS, RAF, or MEK.

In some embodiments of the method of treating acute myeloid leukemia, the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor).

In some embodiments of the method of treating acute myeloid leukemia, the cancer is MAPKm/MAPKi naive pan-tumor.

In some embodiments of the method of treating acute myeloid leukemia, the subject in need of treatment does not experience serious side effects during the 28-day cycle.

In some embodiments of the method of treating acute myeloid leukemia, the subject in need of treatment does not experience a grade 3, 4, or 5 adverse event during the 28-day cycle.

Example

Example 1 - Phase 1b/2 open-label study of Compound 1 in patients with advanced or metastatic solid tumors

study design

Compound 1 in the form of a pharmaceutical composition was administered as monotherapy to subjects with solid tumors in an open-label, multicenter clinical study. After a screening period, eligible subjects were enrolled and treated with a pharmaceutical composition containing Compound 1 as monotherapy until meeting another criterion for disease progression, unacceptable toxicity, or discontinuation of treatment.

The study began with Part A dose escalation of Compound 1 administered as BID-QW as monotherapy, and Part B, further characterization of the activity of Compound 1 administered with 250 mg of QW RD, to be opened simultaneously. Once the monotherapy MTD or RD from Part A was determined, dose expansion of Compound 1 monotherapy BID-QW was initiated in Part C until there was an acceptable safety and PK/PD profile.

All patients underwent a screening evaluation within 30 days prior to the first dose of Compound 1. Each treatment cycle consists of a 4-week (28-day) treatment period.

This study was divided into three parts as described below.

Part A

Part A evaluated Compound 1 as monotherapy administered as BID-QW over a 28-day treatment cycle using a rolling 6 dose escalation design to enroll patients into the study.

Dose levels tested were 50, 100, and 125 mg BID administered QW per day. The starting dose was 50 mg BID-QW, which corresponds to approximately half the weekly RD of 250 mg QW. Treatment cycles were every 4 weeks (28 days).

The Rolling 6 design was used to register in Part A. 2 to 6 patients, depending on the number of patients enrolled at the current dose level, the number of patients experiencing dose-limiting toxicities (DLTs) at the current dose level, and the number of patients pending full DLT evaluation at the current dose level. can be registered at the capacity level at the same time. Enlargement was stopped when a cohort of six was enrolled or study endpoints were met. Dose level allocation was based on the number of patients currently enrolled in the cohort, the number of DLTs observed, and the number of patients at risk of developing DLTs (i.e., patients enrolled but did not complete the DLT assessment period). For example, if three patients are enrolled in the same dose cohort, and each passes the DLT evaluation period without a reported DLT, the dose can be increased and subsequent patients enrolled at the next higher dose level. If any of the first three patients failed the DLT assessment period or one DLT was observed, subsequent patients were entered at the same dose level. Finally, if 2 or more DLTs were observed, the dose level was reduced. This process was repeated for patients 5 and 6. Instead of stopping ramp-up after every 3 patients, ramp-up only stopped when the cohort of 6 was filled. When patients could not be evaluated for DLT, they were replaced by the next available patient if the increment or decrement rules were not met at the time the next available patient was enrolled in the study. To ensure that more subjects than necessary are not exposed to potentially unsafe doses, a rolling 6 design was applied to the interim safety review.

Sequential dose levels received increasing doses of Compound 1 until at least one of the following criteria was met:

a. MTD has been exceeded

b. RD is defined

c. PK insignificant (defined as no substantial increase in exposure despite administration of increasing doses)

d. The sponsor has decided to forgo further dose escalation (e.g., based on strong antitumor activity at the current dose level).

Before at least one of the above criteria was met, dose escalation proceeded independently within Part A.

Part B (Dose Expansion, 250 mg QW Schedule)

Part B evaluates the safety, PK, PD, and clinical activity of Compound 1.

To evaluate the effect of a high-fat diet on the PK of compound 1, a pilot food effect substudy was conducted in approximately 10 patients at a designated location.

Part C (Capacity Expansion, BID-QW Schedule)

Part C evaluates the safety, PK, PD, and preliminary clinical activity of Compound 1 in the following groups.

Group 1: Patients with solid tumors (stage I to 16, stage II to 15) with any documented activating mutation(s) in the MAPK pathway, excluding CRC and NSCLC, who have not previously received a MAPK inhibitor until)

Group 2: Patients with pancreatic cancer (stages I to 16, stages II to 15) with any documented activating mutation(s) in the MAPK pathway who have not previously received a MAPK inhibitor.

Group 3: Patients with NSCLC (stage I to stage 16, stage II to 15) with any documented activating mutation(s) in the MAPK pathway who have not previously received a MAPK inhibitor.

Group 4: Patients with documented BRAF V600 melanoma (stage I to 16, stage II to 15) who previously received a BRAF inhibitor.

Group 5: Patients with documented BRAF V600 NSCLC (stage I to 160, stage II to 15) who previously received BRAF inhibitors.

Group 6: Patients with KRAS G12C NSCLC who previously received G12C inhibitors (stages I to 16, stages II to 15)

For each group defined above that passed the stage I gate with ORR≥10%, stage II patients were enrolled.

study treatment

In Part A, Compound 1 was administered as monotherapy BID-QD over 28 day cycles. Part A consists of multiple dose escalation cohorts. The starting dose for Part A was 50 mg BID-QW.

In Part B, Compound 1 was administered as monotherapy QW over consecutive 4 week cycles at a dose of 250 mg QW.

In Part C, Compound 1 was administered as monotherapy BID-QW over 28 day cycles. The dose level administered in Part C was the monotherapy RD as determined in Part A.

Within these parts, sample size was calculated based on enrollment of the number of evaluable patients summarized in the table below.

Based on the clinical studies described above, a favorable BID-QW dosing schedule was identified.

medicine

Compound 1 pharmaceutical product was supplied as an immediate release oral dosage formulation in the form of 10 mg or 50 mg tablets for oral administration. Tablets contained 10 mg or 50 mg of Compound 1 with the inert excipients hydroxypropyl cellulose, mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, and Opadry White cosmetic coating.

Compound 1 was stored at room temperature (20 20-25° C. [68-77° F.]) with an acceptable deviation of 15-30° C. (59-86° F.) and tested and monitored periodically during acceptable shelf life.

Example 2:

Both QW and QD therapies were evaluated in a first-in-human (FIH) phase 1 study. Data indicate that QW is preferable to QD due to better efficacy and less frequent skin toxicity. Observed data suggest that having uninterrupted coverage of IC ₉₀ for 1-2 days can improve cancer cell killing, maintaining trough concentration (C _trough ) below IC ₅₀ can aid normal cell recovery. This indicates that tolerability can be improved.

Based on available Compound 1 human PK data, a population PK model was developed to characterize PK. Using the developed PK model, simulations were performed to compare the PK performance of different dosing regimens (see Figure 1). Simulations show that compared to QD dosing, QW and BID-QW regimens extended the duration above IC ₅₀ while maintaining C _trough near or below IC ₅₀ to provide treatment interruption to normal cells. Additionally, compared to QW, BID-QW is expected to have lower C _max and comparable C _avg and C _min . With a lower C _max , the BID-QW regimen may further improve C _max derived tolerability while maintaining comparable efficacy compared to the QW regimen.

Claims (25)

A method of treating cancer in a subject in need of treatment for cancer, comprising:
Compound 1 , or a pharmaceutically acceptable salt thereof,
A method in which compound 1 is administered twice a day, once a week (BID-QW). The method of claim 1, wherein the salt of Compound 1 is a mandelic acid salt. 3. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle. The method according to any one of claims 1 to 3, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 28-day cycle. How to do it. The method according to any one of claims 1 to 3, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on days 1, 8, and 15 of a 28-day cycle. The method of any one of claims 1 to 5, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, and 23-28 of a 28-day cycle. Method in which it is not administered to. 3. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 35-day cycle. The method of claim 7, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle. The method of claim 7 or 8, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 2-7, 9-14, 16-21, 23-28, and 30-35 of a 28-day cycle. A method that is not administered to work. The method of any one of claims 1 to 9, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 300 mg twice a day, once a week (BID-QW). Method by which it is administered. The method of any one of claims 1 to 10, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 250 mg twice a day, once a week (BID-QW). Method by which it is administered. The method of any one of claims 1 to 11, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg to about 150 mg twice a day, once a week (BID-QW). Method by which it is administered. The method of any one of claims 1 to 11, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about A method wherein the method is administered in an amount of 175 mg, about 200 mg, about 225 mg, or about 250 mg twice a day, once a week (BID-QW). 14. The method of any one of claims 1 to 13, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice per day. A method in which the method is administered once a week (BID-QW). 15. The method of any one of claims 1-14, wherein the cancer comprises at least one cancer cell with one or more activating mutations in the MAPK pathway. 15. The method of any one of claims 1 to 14, wherein the cancer is a mitogen activated protein kinase (MAPK) pathway driven cancer. 17. The method of claim 16, wherein the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer. 15. The method of any one of claims 1-14, wherein the cancer comprises at least one cancer cell caused by deregulated ERK. 16. The method of any one of claims 1-15, wherein the cancer has at least one mutation in RAS, RAF, or MEK. 20. The method of any one of claims 1-19, wherein the subject has not previously received a MAPK pathway inhibitor (e.g., a KRAS inhibitor, a BRAF inhibitor, a MEK inhibitor, or an ERK inhibitor). The method of any one of claims 1 to 20, wherein the cancer is colorectal cancer (CRC), pancreatic adenocarcinoma (PDAC), cholangiocarcinoma cancer, appendix cancer, stomach cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer. A method that is cancer, uterine cancer, or acute myeloid leukemia (AML). 21. The method of any one of claims 1-20, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, or colorectal cancer (CRC). 23. The method of any one of claims 1 to 22, wherein the cancer is MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive pancreatic cancer, MAPKm/MAPKi naive NSCLC, BRAFi treated V600 NSCLC, BRAFi treated V600 melanoma, or KRAS. Methods for Treated G12C NSCLC. 24. The method of any one of claims 1-23, wherein the subject in need of treatment for cancer does not experience serious side effects during the 28-day cycle. 24. The method of any one of claims 1 to 23, wherein the subject in need of treatment for cancer does not experience grade 3, 4 or 5 adverse events during the 28 day cycle.